This invention relates to a new class of cephem derivatives and a process for preparing the same. More particularly, it relates to a cephem compound which is a new synthetic intermediate useful for various cephalosporin antibiotics having a methoxy group at the 7.alpha.-position thereof and a new process for preparing the said cephem compound. Still more particularly, this invention can provide a cephem compound having a methoxy group at the 7.alpha.-position thereof and a new process for introducing a methoxy group into a cephalosporin moiety at the 7.alpha.-position thereof.
As a group of cephalosporin-type antibiotic substances having a methoxy group at the 7.alpha.-position thereof, cephamycin-type antibiotics have been found to be naturally present and they have also been found to exhibit an excellent antibiotic activity by reason of the characteristic chemical structure of having a methoxy group at the 7.alpha.-position thereof. Since then, there have been synthesized many 7.alpha.-methoxycephalosporin derivatives. On the other hand, various studies have been made on a new process for chemically introducing a methoxy group into a cephem ring at the 7.alpha.-position thereof.
Some of these new derivatives have already been given with an established evaluation as an excellent antibiotic substance and practically applied as a chemotherapeutic agent for clinical use. Accordingly, a chemical process for introducing a methoxy group into a cephalosporin skeleton at the 7.alpha.-position thereof has been regarded as being commercially of utmost importance and there have hitherto been proposed various processes therefor. Illustrative examples thereof may include the following processes:
(1) The process, namely acylimine process, wherein a 7(or 6)-acylaminocephalosporin (or penicillin) is reacted with a positive halogen compound such as tert-butylhypochlorite in the presence of a strong base to form the corresponding acylimino compound followed by addition of methanol to the so formed compound (J. Am. Chem. Soc., 95 2401 (1973)).
(2) The process, namely carbanion process, wherein the amino group at the 7(or 6)-position is converted to Schiff base, the corresponding carbanion at the 7(or 6)-position is formed from the Schiff base by the action of a strong base, the said carbanion is reacted with a methanethiosulfonate or a positive halogen compound to form a 7.alpha.(or 6.alpha.)-methylthio- or halo derivative and then the latter derivative is converted to the corresponding 7.alpha.(or 6.alpha.)-methoxy derivative with methanol (J. Org. Chem., 38, 943 (1973)).
(3) The methoxy-introducing process wherein the Schiff base of the 7(or 6)-amino group with 3,5-di-tert-butyl-4-hydroxybenzaldehyde is oxidized to the quinoneimine form and then methanol is added to the said imine form (Tetrahedron Letters., 1975, 2705).
(4) The process wherein an .alpha.-halo- or .alpha.,.alpha.-dihaloacetamidocephalosporin (or penicillin) or the vinylog thereof is converted to the corresponding iminohalogenated form, the imino ether is derived from the latter form by the substitution of the halogen with methanol, the said imino ether is converted to the corresponding vinyl imine by a 1,4-dehydrohalogenation reaction with a strong base and 1,4-addition of methanol to the said vinyl imine is conducted to introduce a methoxy group at the 7.alpha.(or 6.alpha.)-position thereof (Tetrahedron Letters., 1976, 1307).
(5) The process wherein a 7(or 6)-sulfenamidocephalosporin (or penicillin) is oxidized to the corresponding sulfenimine derivative and methanol is added to the said derivative (J. Am. Chem. Soc. 99, 5505 (1977)).
(6) The process comprising diazotization of the 7(or 6)-amino group and subsequent addition reaction of an azide compound, e.g., a halogen azide to the diazo form (J. Am. Chem. Soc., 94, 1408 (1972)).
However, the above-recited processes are not always said to be complete without any defaults and it is the present situation that there have been made continuous studies on a variety of new or improved processes for a industrially satisfactory process.
For instance, the above processes have the following defects or difficulties and hence there has been desired a development of a far more excellent process.
The above process (1) has a defect that oxidized by-products tend to be produced owing to the strong oxidizing agent employed if there is present a side-chain liable to be oxidized, in particular, a side-chain containing a sulfide bond. The above processes (1), (2) and (4) involve difficult points that a specific reaction condition such as an extremely low temperature for the reaction (namely, -78.degree. C.) should be required and a strong base, such as lithium methoxide and the like should be employed, which may readily cause a .beta.-lactam ring cleavage. The above processes (3) and (5) involve heterogenous reaction employing a large excess of a metal oxide (namely, a solid phase), but the processes show such a difficult point that it is difficult to control such heterogenous reaction if practised in an industrial scale. The above process (6) shows such defects that addition of the azide compound is not stereo-selective with a yield being poor, that long and complicated reaction pathway is needed and so on.